Genetic Susceptibility and Biomarkers of Platinum-related Toxicities

摘要 铂化合物是世界上使用最广泛的细胞毒性药物。每年超过580万 患者被诊断为癌症，一线治疗可能包括铂类药物。尽管结束了 经过30年的使用，几乎没有什么方法可以识别出有铂致耳毒性或神经病变风险的患者 可能会被提供替代疗法或减少剂量的方案。对于必须接受铂金治疗的患者，没有 批准的预防措施和针对这些毒性的治疗很少。为了帮助填补这些重要的空白，在我们最初的项目中 期间，我们建立了第一个特征良好的临床队列，超过2,000名睾丸癌幸存者(TCS)通过 均质顺铂为主的化疗(不含其他耳毒性/神经性药物)，并进入 耳毒性和神经病的遗传学。我们最初的项目阶段非常高效。我们出版了16篇稿件(3 发表在《临床肿瘤学杂志》上)，以及其他3项正在审查中的研究。我们的基线横断面结果显示，80%的 我们的患者在听力测试中有听力损失，五分之一的患者被归类为严重到深度(听力水平 建议使用艾滋病)；56%患有神经病；40%患有耳鸣。我们发现耳聋基因WFS1中的一个SNP 与听力损失相关(P=1.4×10~(-8))也与顺铂剂量有显著交互作用，因此具有潜在的应用价值 临床影响预测易感性。在年轻的中位年龄(37岁)，38%的TC已经患有≥3不良健康 结果(范围1-11)。考虑到这一早期的负担，关键的悬而未决的问题仍然存在，并将在下一次讨论中得到解决 格兰特循环：(1)铂毒性纵向轨迹的表征，包括共病的作用； 可改变的危险因素和残留的血清铂水平；(2)毒性对健康相关生活质量和 患者功能；以及(3)进一步阐明基因变异在铂中毒中的作用，以确定高危 子组。我们的目标是：目标1.描述铂相关耳毒性和神经病的纵向轨迹， 重复测听，并首次扩大数据收集范围，以包括一套全面的物理和 心理社会领域，为最终制定技术咨询服务后续行动的循证指南提供信息；目标2。 首次评估顺铂相关性听力损失、耳鸣和神经病变的影响及其严重程度 患者的身体、情绪和社交功能；目标3.确定其他易使患者发病的基因变异 与铂相关的耳毒性和神经病，并通过基因分型影响残留血清铂水平 和整个外显子组测序。影响：来自我们独特的临床队列的研究结果将提供第一个 对任何大型均质治疗队列中与铂相关的多种毒性进行全面、纵向的评估 并帮助最终制定以循证为基础的TCS跟踪指南 向上。我们的发现也将为开发顺铂的预防和干预策略提供基础。 相关的毒性不仅与生活质量的严重损害有关，而且与大量的发病率有关。

ABSTRACT Platinum compounds are the most widely used group of cytotoxic drugs worldwide. Each year more than 5.8 million patients are diagnosed with a cancer for which first-line therapy can potentially include platinating agents. Despite over 30 years of use, there are few means of identifying patients at risk for platinum-induced ototoxicity or neuropathy who might be offered alternative therapy or reduced-dose regimens. For patients who must receive platinum, there are no approved preventive measures and few therapies for these toxicities. To help fill these important gaps, in our initial project period, we established the first well-characterized clinical cohort of over 2,000 testicular cancer survivors (TCS) cured with homogeneous cisplatin-based chemotherapy (without other ototoxic/neuropathic drugs) and made inroads into the genetics of ototoxicity and neuropathy. Our initial project period was highly productive. We published 16 manuscripts (3 in the Journal of Clinical Oncology), plus 3 others under review. Our baseline, cross-sectional results showed that 80% of our patients had hearing loss on audiometric testing, with 1 in 5 classified as severe-to-profound (a level at which hearing aids are recommended); 56% had neuropathy; and 40% had tinnitus. We found that a SNP in deafness gene WFS1 that was related to hearing loss (P=1.4x10-8) also showed a significant interaction with cisplatin dose, thus having potential clinical impact to predict susceptibility. At a young median age (37 years), 38% of TCS already had ≥3 adverse health outcomes (range 1-11). Given this early burden, critical unanswered questions remain and will be addressed in the next grant cycle: (1) characterization of the longitudinal trajectory of platinum toxicities, including the role of comorbidities, modifiable risk factors, and residual serum platinum levels; (2) the impact of toxicities on health-related quality of life and patient functioning; and (3) further elucidation of the role of genetic variation in platinum toxicities to identify high-risk subgroups. Our aims are: Aim 1. Characterize the longitudinal trajectory of platinum-related ototoxicity and neuropathy, repeating audiometry, and expanding data collection for the first time to include a comprehensive set of physical and psychosocial domains to inform the eventual development of evidence-based guidelines for TCS follow-up; Aim 2. Evaluate for the first time the impact of cisplatin-related hearing loss, tinnitus and neuropathy and their severity on physical, emotional and social patient functioning; Aim 3. Identify additional genetic variation that predisposes patients to platinum-related ototoxicity and neuropathy and that influences residual serum platinum levels through genotyping and whole exome sequencing. IMPACT: Findings derived from our unique clinical cohort will provide the first comprehensive, longitudinal assessment of multiple platinum-related toxicities in any large, homogenously treated cohort of adult-onset cancer survivors and help inform the eventual development of evidence-based guidelines for TCS follow- up. Our findings will also provide the basis for the development of preventive and interventional strategies for cisplatin- related toxicities associated not only with significant impairment of quality of life, but substantial morbidity.